Precocious puberty: Diagnosis and evaluation

INTRODUCTION — 

Precocious puberty is the onset of pubertal development at an age that is 2 to 2.5 standard deviations (SD) earlier than population norms. The cause of precocious puberty may range from a variant of normal development (eg, isolated premature adrenarche or isolated premature thelarche) to pathologic conditions with significant risk of morbidity and even death (eg, malignant germ-cell tumor or astrocytoma).

The clinician faced with a child who presents with early development of secondary sexual characteristics should consider the following questions:

●Is the child too young to have reached the pubertal milestone in question? – To answer this question, the clinician needs to know the normal ages for pubertal milestones and how to distinguish normal from abnormal development.

●What is causing the early development? – To answer this question, the clinician ascertains whether the development of secondary sexual characteristics is attributable to androgen and/or estrogen effects and whether the source of sex hormone is centrally mediated through the hypothalamic-pituitary-gonadal axis, from an autonomous peripheral origin, or has an exogenous basis.

●Is therapy indicated, and, if so, what therapy?

The definition of precocious puberty and its causes and evaluation will be reviewed here. The treatment of precocious puberty is discussed separately. (See "Treatment of precocious puberty".)

DEFINITION — 

Precocious puberty is traditionally defined as the onset of breast development before the age of eight years in females and testicular enlargement before the age of nine years in males [1]. These limits are chosen as they are 2 to 2.5 standard deviations (SD) below the mean age of onset of puberty. In most populations, attainment of pubertal milestones approximates a normal distribution, with a mean age of onset of puberty of approximately 10.5 years in females and 11.5 years in males (figure 1A-B) and an SD of approximately one year [1-9]. (See 'Which children should be evaluated?' below.)

NORMAL PUBERTAL DEVELOPMENT — 

The hypothalamic-pituitary-gonadal axis is biologically active in utero and briefly during the first week of life. It then becomes more active again during infancy, with peak activity between one and three months of age [10]. This state yields sex steroid levels comparable with those seen in early-to-mid puberty but without peripheral effects. In males, gonadotropin concentrations then decrease to prepubertal levels by six to nine months of age. In females, luteinizing hormone (LH) levels decrease at approximately the same time as in males, but the follicle-stimulating hormone (FSH) concentrations can remain elevated into the second year of life. This hypothalamic-pituitary-gonadal activity during infancy is often referred to as the "mini puberty of infancy"; its biologic relevance is unknown.

The neonatal stage is followed by active suppression of the hypothalamic-pituitary-gonadal axis until puberty occurs. The physiologic and genetic mechanisms that affect timing of pubertal maturation are discussed separately. (See "Normal puberty", section on 'Physiology and endocrinology of puberty'.)

In 1969 and 1970, Marshall and Tanner defined the stages of normal pubertal development in children and adolescents, known as sexual maturity ratings or "Tanner stages" (picture 1 and figure 2A-B) [2,3]. These studies reported that the first sign of puberty in females was breast development at an average age of 11 years (thelarche), followed by pubic hair growth (pubarche), and then menarche. In males, the first sign was testicular enlargement at an average age of 11.5 years, followed by penile growth and pubic hair growth. (See "Normal puberty".)

Since these reports by Marshall and Tanner, several studies in the United States and other countries suggest that children, especially those with an increased body mass index, enter puberty at a younger age [4,5,7-9,11,12]. These data and the proposed explanations for the trends are discussed separately. (See "Normal puberty", section on 'Trends in pubertal timing'.)

The approach to identifying children in need of a clinical evaluation for early puberty is discussed elsewhere. (See 'Definition' above and 'Which children should be evaluated?' below and "Endocrine-disrupting chemicals", section on 'Precocious puberty'.)

EPIDEMIOLOGY — 

Although much has been made of puberty occurring in younger children, describing epidemiologic trends in precocious puberty may be challenging. There are several reasons for this:

●Challenges in estimating prevalence – Estimates of the prevalence of precocious puberty differ markedly depending on the population studied. Using the traditional definition of precocious puberty as the development of secondary sexual characteristics before age eight years in females and nine years in males (2 to 2.5 standard deviations [SD] below the average age of pubertal onset in healthy children), one would expect that the prevalence rate should be around 2 percent (ie, 2 in every 100 children). In addition, the strong female predominance of children undergoing medical evaluations for precocious puberty in the United States has no clear biologic explanation; referral bias may also contribute to this finding [11,13-15]. As examples:

•In a population-based study of data from Danish national registries 1998 to 2017, the incidence of precocious puberty over the entire time period was 11.5 per 10,000 females and less than 2 per 10,000 males [13,16]. Of note, there has been a significant increase in the annual incidence over the study time period, particularly in those with central precocious puberty (CPP).

•In a retrospective review of 104 consecutive children referred for evaluation of precocious puberty in the United States, 87 percent were female [14].

•In Korea, increased rates of CPP in males and females, as measured by gonadotropin-releasing hormone (GnRH) agonist insurance claims, have been reported [17].

●Challenges related to using race/ethnicity in definitions of precocious puberty – It is important to incorporate all available clinical information into the decision regarding the evaluation of a child with precocious puberty. Although some guidance has suggested that race/ethnicity should be incorporated into decisions about thresholds for the evaluation for precocious puberty [18,19], the validity of this approach has not been demonstrated. This lack of validity is likely because associations between genetic ancestry and the timing of puberty [20] are relatively weak, are not observed in all population groups, and decrease with population diversification. Moreover, racial/ethnic groups represent social constructs that are often poor surrogates for genetic ancestry.

For these reasons, it remains unclear to what degree race/ethnicity is an independent modifier as opposed to a marker for other factors that impact pubertal timing, such as body mass index (BMI), exposure to endocrine-disrupting chemicals, and/or other social determinants of health [21]. As an example, a longitudinal study in the United States demonstrated a median age of breast development at 8.8 years in Black girls, 9.3 years in Hispanic girls, and 9.7 years in Asian and White non-Hispanic girls [15]. BMI accounted for a greater proportion of this variance (14 percent) than race/ethnicity (4 percent).

More data are needed to understand trends in the prevalence of precocious puberty and the relative contribution of genetic and environmental factors to risk for early pubertal development. (See "Normal puberty", section on 'Factors influencing pubertal timing' and "Endocrine-disrupting chemicals", section on 'Precocious puberty'.)

CLASSIFICATION BASED ON ETIOLOGY — 

Precocious puberty can be classified based on the underlying pathologic process (algorithm 1).

Central precocious puberty (CPP) — CPP (also known as gonadotropin-dependent precocious puberty or true precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. Although the onset is early, the pattern and timing of pubertal events is usually typical. However, children with CPP have accelerated linear growth for age, advanced bone age, and pubertal levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). CPP is pathologic in 20 to 75 percent of cases in males [22,23], compared with 10 to 20 percent in females (table 1) [24-26]. (See 'Causes of central precocious puberty' below.)

Peripheral precocious puberty — Peripheral precocious puberty (also known as peripheral precocity, gonadotropin-independent precocious puberty) is caused by excess secretion of sex hormones (estrogens or androgens) from the gonads or adrenal glands, exogenous sources of sex steroids, or ectopic production of gonadotropin from a germ-cell tumor (eg, human chorionic gonadotropin [hCG]) (table 2). Some experts prefer "precocity" instead of puberty because true puberty requires activation of the hypothalamic-pituitary-gonadal axis, as occurs in CPP. Peripheral precocity may be appropriate for the child's sex (isosexual) or inappropriate, with virilization of females and feminization of males (contrasexual). (See 'Causes of peripheral precocious puberty' below.)

Benign or nonprogressive pubertal variants — Benign clinical pubertal variants include isolated estrogen-mediated breast development in females (premature thelarche) or isolated androgen-mediated sexual characteristics (such as pubic and/or axillary hair, acne, and apocrine odor) in males or females (premature adrenarche, which results from early activation of the hypothalamic-pituitary-adrenal axis, as confirmed by mildly elevated levels of dehydroepiandrosterone sulfate [DHEAS] for age) (table 3). Both of these conditions can be a variant of normal puberty. However, repeat clinical examination is warranted to ensure that the diagnosis is correct and there is no rapid and/or expanded pubertal progression (ie, no evidence of both estrogen- and androgen-mediated effects). (See 'Benign or nonprogressive pubertal variants' below.)

CAUSES OF CENTRAL PRECOCIOUS PUBERTY — 

Central precocious puberty (CPP) is caused by early maturation of the hypothalamic-pituitary-gonadal axis.

Idiopathic (most common) — CPP is idiopathic in 80 to 90 percent of cases of females but in only 25 to 80 percent of males [22-26]. In some cases, especially those with other affected family members, designation as idiopathic CPP may be due to the presence of genetic variants that are associated with early puberty. (See "Normal puberty", section on 'Physiology and endocrinology of puberty'.)

Rare causes — Several rare disorders cause CPP.

Central nervous system and pituitary lesions — Because CPP can be associated with discernible lesions of the central nervous system (CNS), a condition referred to as neurogenic CPP (table 1), contrast-enhanced magnetic resonance imaging (MRI) is often recommended, even in the absence of clinically evident neurologic abnormalities [22,24,26]. However, the low prevalence of CNS lesions in females with the onset of puberty that begins after age six years raises the question if all females in this age group need imaging [25].

Many different types of intracranial disturbances can cause precocious puberty, including the following:

•Hamartomas – Hamartomas of the tuber cinereum are benign tumors that can be associated with gelastic (laughing or crying) and other types of seizures [27]. They are the most frequent type of CNS tumor to cause precocious puberty in very young children, although in most cases, the mechanism by which these tumors lead to CPP is unknown.

•Other CNS tumors – Other CNS tumors associated with precocious puberty include astrocytomas, ependymomas, pinealomas, and optic and hypothalamic gliomas [24]. Precocious puberty in patients with neurofibromatosis is usually, but not always, associated with an optic glioma [28]. (See "Clinical manifestations and diagnosis of central nervous system tumors in children".)

•CNS irradiation – Precocious puberty is a rare complication of CNS irradiation, but, when it occurs, it is commonly associated with growth hormone (GH) deficiency [29,30]. In this setting, regardless of height velocity, the GH axis should be evaluated. If testing shows GH deficiency, the patient should be treated with GH combined with GnRH agonist therapy. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Growth hormone deficiency'.)

•Other CNS lesions – Precocious puberty has been associated with hydrocephalus, cysts, trauma, CNS inflammatory disease, and congenital midline defects, such as optic nerve hypoplasia. (See "Congenital and acquired abnormalities of the optic nerve", section on 'Hypoplasia'.)

•Pituitary gonadotropin-secreting tumors — These tumors are extremely rare in children and are associated with elevated levels of LH and occasionally FSH [31].

Genetic variants — Pathogenic variants in several genes, as well as abnormal epigenetic modification (ie methylation) of certain genetic regions, have been associated with CPP [32]. Although each appears to be present in only a minority of spontaneous cases of CPP, pathogenic genetic variants have been more commonly found in familial CPP cohorts [33-35]:

●Gain-of-function variants in the kisspeptin 1 gene (KISS1) [36] and the gene for its G protein-coupled receptor (KISS1R, formerly known as GPR54) [37] have been implicated in the pathogenesis of some cases of CPP, while pathogenic loss-of-function variants in KISS1R can cause hypogonadotropic hypogonadism. These observations demonstrate that KISS1/KISS1R is essential for GnRH physiology and for initiation of puberty [38].

●CPP also can be caused by pathogenic loss-of-function variants in MKRN3 (the gene encoding makorin ring finger protein 3), an imprinted gene in the Prader-Willi syndrome critical region (15q11-q13). The decline of hypothalamic MKRN3 expression in mice [39] and serum MKRN3 protein levels in females prior to the onset of puberty [40] indicate that MKRN3 plays an important role in repressing pubertal initiation. Thus, pathogenic loss-of-function variants in this gene would lead to diminished inhibition and early onset of puberty. Paternally inherited loss-of-function variants in MKRN3 have been reported in up to 46 percent of familial cases of CPP and nearly 10 percent of idiopathic cases [39,41-44].

●CPP is a phenotypic feature of several genetic syndromes including Silver-Russell syndrome and Temple Syndrome [45], both of which are also characterized by prenatal growth restriction and short stature. Silver-Russell syndrome is discussed elsewhere (See "Causes of short stature", section on 'Silver-Russell syndrome'.)

Temple syndrome is caused by decreased expression of genes in the paternally-inherited 14q32.2 chromosomal region [46], which may be caused by deletions, abnormal methylation or overexpression of the maternal allele. CPP in these patients is likely related to decreased expression of a specific gene in this region, DLK1. This is based on reports of paternally inherited loss-of-function variants in DLK1 causing CPP without associated syndromic features in a small number of patients [47,48].

A Japanese cohort of 90 children with CPP found Temple syndrome-associated alterations in expression of the genes in the 14q32.2 region were the most frequently identified genetic change, occurring in eight patients (8.9 percent). Most of these patients were born small for gestational age (SGA), had a lower mean height percentile than patients without Temple syndrome-associated genetic abnormalities, and had developmental delays [32].

●Variants in the MECP2 (Methyl-CpG-Binding Protein 2) gene have been identified as X-linked dominant causes of CPP in a small number of female children, with a median age of thelarche onset of 5.4 years [49]. In some individuals, CPP was associated with mild neurodevelopmental disorders (eg autism), but other patients did not exhibit a neurodevelopmental phenotype.

Pubertal timing in the general population may be influenced in part by less severe variants in these genes. As an example, polymorphisms in the DLK1 gene as well as in MKRN3 are associated with variation in the age of menarche in large genome-wide association studies [50]. An ongoing area of investigation focuses on the contribution of these and other common variants to pubertal timing [51]. Genetic factors involved in pubertal onset are discussed separately. (See "Normal puberty", section on 'Physiology and endocrinology of puberty'.)

Early exposure to endogenous sex steroids — Children who have been exposed to high serum levels of endogenous estrogen or androgen (eg, those with McCune-Albright syndrome and poorly controlled congenital adrenal hyperplasia) may sometimes develop superimposed CPP, either from the priming effect of the peripheral precocity-derived sex steroid on the hypothalamus or in response to the sudden lowering of the sex steroid levels following improved control of the sexual precocity [52,53]. (See 'McCune-Albright syndrome' below.)

CPP can be treated with a gonadotropin-releasing hormone (GnRH) agonist, which leads to downregulation of the pituitary response to endogenous GnRH, produces a prepubertal hormonal state, and stops the progression of secondary sexual development, accelerated growth, and undue bone age advancement [19]. (See "Treatment of precocious puberty", section on 'Treatment for central precocious puberty'.)

CAUSES OF PERIPHERAL PRECOCIOUS PUBERTY — 

Peripheral precocious puberty (also known as peripheral precocity or gonadotropin-independent precocious puberty) is caused by excess secretion of sex hormones (estrogens and/or androgens) derived either from the gonads or adrenal glands or from exogenous sources (table 2).

Further characterization is based on whether the pubertal characteristics are appropriate for the child's sex (isosexual) or inappropriate, with virilization of females and feminization of males (contrasexual). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are typically suppressed (below or into the prepubertal range) and do not increase substantially with gonadotropin-releasing hormone (GnRH) stimulation.

The approach to treatment for peripheral precocity depends on the cause. GnRH agonist therapy is ineffective, in contrast to patients with central precocious puberty (CPP). (See "Treatment of precocious puberty", section on 'Treatment for peripheral precocity'.)

In the following discussion, the causes of peripheral precocity are described based on sex.

Ovarian disorders (females)

●Ovarian cysts – A functioning follicular cyst of the ovaries is the most common cause of peripheral precocity in females [54]. Affected patients often present with breast development, followed by an episode of vaginal bleeding, which occurs due to estrogen withdrawal once the cyst has regressed. These cysts may appear and regress spontaneously, so conservative management is usually appropriate [55]. Large cysts may predispose to ovarian torsion.

●Ovarian tumors – Ovarian tumors are a rare cause of peripheral precocity in females. Granulosa cell tumors, the most common type, typically present as isosexual precocity; Sertoli/Leydig cell tumors (arrhenoblastoma), pure Leydig cell tumors, and gonadoblastoma may make androgens and cause contrasexual precocity [56-58]. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)

Testicular disorders (males)

●Leydig cell tumors – Leydig cell tumors should be considered in any males with asymmetric testicular enlargement. Even if a distinct mass cannot be palpated and none is evident on ultrasonography, the larger testis should be biopsied if it enlarges during follow-up. These testosterone-secreting tumors are almost always benign and are readily cured by surgical removal [59]. Radical orchiectomy is the most common procedure; however, successful treatment by direct enucleation of the tumor with sparing of the remainder of the testis has been reported [60]. (See "Testicular sex cord stromal tumors", section on 'Leydig cell tumors'.)

●Human chorionic gonadotropin-secreting germ-cell tumors – Germ-cell tumors secrete human chorionic gonadotropin (hCG), which, in males, activates LH receptors on the Leydig cells, resulting in increased testosterone production [61]. The increase in testicular size (usually only to an early pubertal size) is less than expected for the serum testosterone concentration and degree of pubertal development. This discrepancy is because most of the testis is made up of seminiferous tubular elements whose maturation depends on FSH. In females, hCG-secreting tumors do not typically lead to precocious puberty, because activation of both FSH and LH receptors is needed for estrogen biosynthesis [62].

These tumors occur in the gonads, brain (usually in the pineal region), liver, retroperitoneum, and anterior mediastinum, reflecting sites of embryonic germ cells before their coalescence in the gonadal ridge [61,63]. The histology of hCG-secreting tumors ranges from dysgerminoma, which respond readily to therapy, to the more malignant embryonal cell carcinoma and choriocarcinoma. All males with anterior mediastinal germinomas should have a karyotype because these tumors may be associated with Klinefelter syndrome. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors" and "Pathology of mediastinal tumors", section on 'Germ cell tumors'.)

●Familial male-limited precocious puberty – This rare disorder (also known as testotoxicosis) is caused by an activating variant in the LH receptor gene, which results in premature Leydig cell maturation and testosterone secretion [64]. Although inherited as an autosomal dominant disorder, females are not affected clinically, because (similar to hCG-secreting germ tumors) activation of both the LH and FSH receptors is required for estrogen biosynthesis [65]. Also similar to hCG-secreting tumors, the increase in testicular size is usually only to an early pubertal size. Affected males typically present between one to four years of age.

Treatment of this disorder is discussed separately. (See "Treatment of precocious puberty", section on 'Familial male-limited precocious puberty'.)

Both females and males — The following causes of peripheral precocious puberty can occur in either females or males. Physical changes either may be isosexual or contrasexual depending on the sex of the child and the type of sex hormone produced. Excess estrogen will cause feminization, while excess androgen will result in virilization.

McCune-Albright syndrome — McCune-Albright syndrome (MAS; MIM #174800) is a rare disorder defined as the triad of peripheral precocious puberty, irregular café-au-lait ("coast of Maine") skin pigmentation (picture 2), and fibrous dysplasia of bone (image 1) [66,67]. MAS should be considered in females with recurrent formation of follicular cysts and cyclic menses [55]. The skin manifestations and bone lesions may increase over time. In females presenting with vaginal bleeding, the ovarian enlargement has often been mistaken for an ovarian tumor, leading to unnecessary oophorectomy [68]. Females presenting with premature vaginal bleeding should therefore be evaluated for features of MAS to avoid this potential mistake.

The clinical phenotype varies markedly, depending on which tissues are affected by the gene variant, but precocious puberty is the most commonly reported manifestation [69]. As in other forms of peripheral precocity, the sequence of pubertal progression may be abnormal, in that vaginal bleeding often precedes significant breast development [70]. Prolonged exposure to elevated levels of sex steroids may cause accelerated growth, advanced skeletal maturation, and compromised adult height. Although the precocious puberty is typically peripheral in origin, a secondary component of CPP may develop because of sex steroid withdrawal leading to activation of the hypothalamic-pituitary-gonadal axis [71]. (See 'Rare causes' above.)

In males with MAS, while sexual precocity is less common, there is a high prevalence of testicular pathology on ultrasound, including hyper- and hypoechoic lesions (most likely representing areas of Leydig cell hyperplasia), microlithiasis, and focal calcifications [72,73].

Patients with MAS have a somatic (postzygotic) pathogenic variant of the alpha subunit of GNAS, which encodes the Gs protein that activates adenylyl cyclase [74-76]. This pathogenic variant leads to continued stimulation of endocrine function, including precocious puberty, thyrotoxicosis, growth hormone excess (gigantism or acromegaly), Cushing syndrome, and renal phosphate wasting (hypophosphatemic rickets) in various combinations. GNAS variants can be found in other nonendocrine organs (liver and heart) resulting in cholestasis and/or hepatitis, intestinal polyps, and cardiac arrhythmias, respectively [67]. A heightened risk of malignancy has also been reported [77]. Germline occurrences of this mutation would presumably be lethal [74,75,78].

Diagnosis of MAS is generally made based on clinical criteria, but a biopsy of bone lesions for histologic analysis and genetic testing may be used if the diagnosis is not clear based on clinical and radiographic manifestations. (See 'Features of genetic disorders' below.)

Treatment of precocious puberty associated with MAS is described in a separate topic review (see "Treatment of precocious puberty", section on 'McCune-Albright syndrome'). More detailed information, including evaluation and management of associated skeletal abnormalities, renal phosphate wasting and endocrine abnormalities, is described in a guideline from an international consortium [67].

Primary hypothyroidism — Children with severe, long-standing primary hypothyroidism occasionally present with precocious puberty. In females, findings include early breast development, galactorrhea, and recurrent vaginal bleeding, while affected males present with premature testicular enlargement [79,80]. Historically, this has been referred to as the "overlap" or Van Wyk-Grumbach syndrome [79]. The signs of pubertal development regress with thyroxine therapy. (See "Acquired hypothyroidism in childhood and adolescence".)

A proposed mechanism is cross-reactivity and stimulation of the FSH receptor by high serum thyrotropin (thyroid-stimulating hormone [TSH]) concentrations, given that both TSH and FSH share a common alpha subunit [81].

Exogenous sex steroids and endocrine-disrupting chemicals — Feminization, including gynecomastia in males, has been attributed to exposure to topical estrogen in creams, ointments, and sprays. Caretakers using these topical estrogens to treat menopausal symptoms, for example, may inadvertently expose children to the hormones [82,83]. Other possible sources of estrogen exposure include contamination of food with hormones, phytoestrogens (eg, in soy), and over-the-counter remedies such as lavender oil and tea tree oil [84,85].

Similarly, virilization of young children has been described following inadvertent exposure to transdermal preparations of androgen [86,87]. There is ongoing research assessing the influence of endocrine-disrupting chemicals on population trends of earlier onset of puberty as well as their potential role as causative agents of precocious puberty. (See "Endocrine-disrupting chemicals", section on 'Children'.)

Adrenal pathology — Adrenal causes of excess androgen production include androgen-secreting tumors and enzymatic defects in adrenal steroid biosynthesis (congenital adrenal hyperplasia). Forms of congenital adrenal hyperplasia that may be associated with androgen excess include 21-hydroxylase deficiency, 11-beta-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase type 2 deficiency, hexose-6-phosphate dehydrogenase deficiency, and phosphoadenosine phosphosulfate synthase type 2 deficiency. (See "Uncommon congenital adrenal hyperplasias" and "Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children: Clinical manifestations and diagnosis" and "Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children and adolescents".)

Such disorders may present with premature pubarche, although this is much more commonly caused by premature adrenarche. Males with precocious puberty due to adrenal androgens will not have testicular enlargement (testes will be <4 mL testicular volume or <2.5 cm in diameter). Laboratory evaluation will demonstrate elevated adrenal androgens. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and 'Signs of androgen excess' below.)

Adrenal estrogen-secreting tumors can lead to feminization. Rarely, adrenal tumors may produce androgen and estrogen, the latter because of intra-adrenal aromatization of androgen (or production of enough androgen that is peripherally aromatized to estrogen), causing both male and female pubertal changes [88]. (See "Clinical presentation and evaluation of adrenocortical tumors".)

BENIGN OR NONPROGRESSIVE PUBERTAL VARIANTS — 

Early pubertal development fits into this category when the early development of secondary sexual characteristics does not herald underlying pathology and is not followed by progressive development (table 3). However, monitoring for evidence of pubertal progression is important as some children presenting with an apparent benign pubertal variant will instead turn out to have a disorder. As examples, thelarche may be the initial presenting feature of central precocious puberty (CPP) or progressive pubic hair development may herald a form of peripheral precocity.

Premature thelarche (breast development) — Most cases of premature thelarche are idiopathic and present under two years of age (and may even start at birth). Many cases will remit spontaneously, and most others do not progress. However, follow-up is warranted because premature thelarche can represent the initial presentation of true CPP in as many as 10 to 20 percent of children referred to pediatric endocrinology for evaluation [89-91].

●Key features of premature thelarche are:

•Isolated breast development, either unilateral or bilateral – Typically not developing beyond Tanner stage 3

•Absence of other secondary sexual characteristics

•Normal height velocity for age (not accelerated)

•Normal or near-normal bone age

•Serum luteinizing hormone (LH) and estradiol concentrations are typically in the prepubertal range, but one should be cautious in interpreting these levels in children under the age of two years because elevations can be seen as part of the normal transient "mini-puberty of infancy," and CPP can be diagnosed inappropriately (see 'Normal pubertal development' above)

●Affected populations include:

•Neonates – Breast hypertrophy can occur in neonates regardless of sex and is sometimes quite prominent. It is caused by stimulation from maternal hormones and usually resolves spontaneously within a few weeks or months. The breast development may also be associated with galactorrhea ("witch's milk"), which also resolves spontaneously [92]. While in most cases, neonatal thelarche disappears over the first months of life, failure to do so almost never has any pathologic significance. (See "Breast masses in children and adolescents", section on 'Neonates and infants'.)

•Toddlers and children – Premature thelarche occurs in two peaks: one during the first two years of life and the other at six to eight years of age [91], with potentially different underlying pathophysiology accountable for each of these peaks. Postulated mechanisms include transient activation of the hypothalamic-pituitary-gonadal axis with excess follicle-stimulating hormone (FSH) secretion [93]. In infants, soy-based formulas have been implicated, although the evidence is weak and may represent only a slower waning of breast tissue during infancy [94,95]. Use of lavender oil, tea tree oil, or hair care products that contain placental extract has also been implicated in some cases of premature thelarche [84]. In most instances, no cause can be found.

In most cases, premature thelarche requires only reassurance. However, the patient should be examined for other signs of pubertal development and growth data should be plotted; an accelerated height velocity may be indicative of progressive puberty and requires further evaluation. To identify patients with progressive puberty, patients should be monitored for several months for evidence of pubertal progression. (See 'Evaluation' below.)

Premature adrenarche — Premature adrenarche is characterized by the appearance of pubic and/or axillary hair, apocrine odor, and/or acne (pubarche) prior to the age of eight years in females and nine years in males, in conjunction with a mild elevation in serum dehydroepiandrosterone sulfate (DHEAS) for age. Premature adrenarche is more common in children who are female, born small for gestational age, Black or Hispanic (at least in the United States), and/or have obesity and insulin resistance [18]. Premature adrenarche is considered a variant of normal development but may be a risk factor for later development of polycystic ovary syndrome in females. (See "Premature adrenarche" and "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome (PCOS) in adolescents".)

In the child presenting with pubic hair alone (isolated pubarche) and other features of premature adrenarche, monitoring for the development of other secondary sexual characteristics (breast or testicular enlargement) is important to ensure that the child's presentation is not the first feature of CPP or a form of peripheral precocity. Premature adrenarche can be associated with mild growth acceleration and advance in bone age. In children with progressive virilization or with a more advanced bone age (>2 standard deviations [SD] beyond chronologic age), further investigation for other causes of early pubertal development should be considered. (See "Premature adrenarche", section on 'Initial evaluation of premature pubarche'.)

Pubic hair of infancy — Pubic hair of infancy is usually a benign condition where infants present with isolated genital hair, usually finer in texture than typical pubic hair and located along the labia or over the scrotum (rather than on the pubic symphysis) [96-98]. The steroid profile of these infants demonstrates normal or mildly elevated DHEAS concentrations for age. Unlike premature adrenarche, the condition is transient and the hair typically disappears within 6 to 24 months [99]. In the absence of progressive development of further genital hair or other secondary sexual characteristics during follow-up, extensive evaluation is not needed.

Benign prepubertal vaginal bleeding — Benign prepubertal vaginal bleeding is characterized by the presence of isolated, self-limited vaginal bleeding in the absence of other secondary sexual characteristics [100]. The underlying etiology is unknown, but potential mechanisms include increased endometrial sensitivity to circulating estrogens or transient stimulation of the hypothalamic-pituitary-gonadal axis [101]. Pelvic ultrasonography is normal, and gonadotropins are prepubertal. Genital or vaginal trauma, infection, and sexual abuse should be excluded. In girls with recurrent episodes of vaginal bleeding, other diagnoses (such as recurrent functional ovarian cysts or McCune-Albright syndrome [MAS]) should be considered. These conditions may not be initially recognized, because vaginal bleeding is associated with regression of the ovarian cyst and, hence, an ultrasound conducted at or after bleeding has occurred may be normal. (See 'McCune-Albright syndrome' above.)

Intermittently or nonprogressive precocious puberty — A subgroup of patients presenting with what clinically appears to be CPP (often with evidence of both gonadarche and pubarche) will either have stabilization or very slow progression in their pubertal signs [102]. The bone age is typically not as advanced compared with children with true CPP, and serum LH concentrations are within the pre- or early-pubertal range, indicating that the hypothalamic-pituitary-gonadal axis is not fully activated and a FSH-predominant response is typically seen if gonadotropin-releasing hormone (GnRH) agonist stimulation testing is performed. Monitoring for evidence of pubertal progression is important to distinguish these children from those with true CPP. In children with nonprogressive precocious puberty, treatment with a GnRH agonist is not needed, because their adult height is not affected (ie, their adult height untreated is concordant with their midparental height) [102,103].

EVALUATION — 

The evaluation is focused on determining the stage of pubertal development, identification of concerning clinical features (if present), and identification of the underlying cause.

Which children should be evaluated? — We suggest careful evaluation of children presenting with signs of secondary sexual development younger than the ages of eight years in females or nine years in males. The level of concern and extent of evaluation should increase with younger age at presentation but decrease in the presence of factors associated with earlier pubertal timing such as increased adiposity or family history of early pubertal development [11,15]. Neither obesity nor racial/ethnic origin obviates the need for careful assessment [104].

Given the trend towards earlier pubertal development in females who are between the ages of seven and eight, a comprehensive history, physical examination, and careful follow-up may be sufficient if the clinical evaluation does not raise any additional concerns [18]. Routine use of younger age cutoffs is controversial raising concerns that they will result in failure to identify some children with true disease [105-107]. The degree and/or rate of pubertal progression should also be taken into account. (See 'Epidemiology' above and 'Evaluation' above and "Normal puberty", section on 'Trends in pubertal timing'.)

●Is the cause of precocity central or peripheral? – The sequence of pubertal development in children with central precocious puberty (CPP) recapitulates normal pubertal development but at an earlier age (figure 1A-B). By contrast, individuals with peripheral precocious puberty have a peripheral source of gonadal hormones and are more likely to display deviations from the normal sequence and/or pace of puberty. As an example, a female who progresses to menstrual bleeding within one year of the onset of breast development is more likely to have ovarian pathology (a cause of peripheral precocity) rather than CPP.

●How quickly is the puberty progressing? – The pace of pubertal development reflects the degree and duration of sex steroid action.

•A rapid rate of linear growth and skeletal maturation (measured as advanced bone age) suggests either peripheral precocity or CPP, with concern raised for a neurogenic cause of CPP if the tempo is abnormally fast (table 4). Pubertal progression would be considered slow if there is minimal or no change in the stage of breast, pubic hair, or genital development during six or more months of observation. Height velocity is considered accelerated if it is more than the 95^th percentile for age (figure 3A-B).

•By contrast, a child with normal linear growth and skeletal maturation (bone age normal or minimally advanced) suggests a benign pubertal variant with low concentrations of sex steroids, rather than true CPP or peripheral precocity.

●Is the precocious puberty because of excess androgen or estrogen? – Are the secondary sexual characteristics virilizing or feminizing? Isolated contrasexual development (isolated virilization in females or isolated feminization in males) excludes central etiologies. While in females the most common cause of virilization is due to excess adrenal androgens, a rare ovarian cause of virilization is ovarian arrhenoblastoma (Sertoli-Leydig cell tumor) [108]. Conversely, a rare testicular cause of feminization is a feminizing Sertoli cell tumor, which may be associated with Peutz-Jeghers syndrome [109]. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults" and "Testicular sex cord stromal tumors", section on 'Sertoli cell tumors'.)

History and physical examination — The evaluation of a patient suspected to have precocious puberty begins with a history and physical examination. In most cases, radiographic measurement of bone age is performed to determine whether there is a corresponding increase in epiphyseal maturation.

●Medical history – The history focuses on when the initial pubertal changes were first noted, as well as the timing of pubertal onset in the parents and siblings. In addition, other questions are directed toward evidence of linear growth acceleration, headaches, changes in behavior or vision, seizures, or abdominal pain (indicative of either a central nervous system [CNS] or ovarian process) and previous history of CNS disease or trauma. The possibility of exposure to exogenous sex steroids (medicinal or cosmetic sources) or compounds with sex steroid-like properties (endocrine-disrupting chemicals, for example) should always be explored [82].

●Physical examination – This includes height, weight, and height velocity (cm/year). Children with benign forms of precocious puberty do not usually display the early growth acceleration pattern that is seen among those with progressive forms of precocious puberty [110]. The physical examination should include assessment of visual fields (a defect suggests the possibility of a CNS mass) and examination for café-au-lait spots (which would suggest neurofibromatosis or McCune-Albright syndrome) (picture 2). (See 'McCune-Albright syndrome' above.)

●Pubertal staging – A physical examination should be performed to determine the sexual maturity rating (Tanner stage) of pubertal development. This means staging breast development in females (picture 1), genital development in males, and pubic hair development in all children (figure 2A-B). In females, the diameter of glandular breast tissue (by direct palpation including compression to differentiate from adipose tissue when warranted) and the nipple-areolar complex should be assessed. In males, measurements are made of the testicular volume (figure 4) [111]. Penile size (stretched length of the non-erect penis, measuring from the pubic bone to tip of glans, excluding the foreskin) is rarely used for monitoring of pubertal progress because penile growth is not an early event in puberty, accurate measurement is difficult and may be awkward for adolescent males, and the "pubertal threshold" for penile-stretched length is not as clear as it is for testicular volume. Accurate measurements of testicular volume are critical to determine whether further radiologic or laboratory testing is necessary. (See "Normal puberty", section on 'Secondary sex characteristics (Tanner stages)' and "Normal puberty", section on 'Pubertal changes'.)

Initial tests — If there is evidence of progressive pubertal development, further evaluation is needed to determine its cause, whether therapy is needed, and, if so, which treatment is appropriate.

The first step is to measure basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), and either estradiol and/or testosterone concentrations. The results are used to differentiate between CPP and peripheral precocity, which then guides additional testing (algorithm 1 and table 4).

Basal serum luteinizing hormone — A good initial screening test to identify activation of the hypothalamic-pituitary-gonadal axis is measurement of basal LH concentration (ideally in the morning), using sensitive immunochemiluminescence assays with a lower limit of detection of ≤0.1 mIU/mL (where mIU = milli-international units) [112]. Results are interpreted as follows:

●LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral precocity or a benign pubertal variant such as premature thelarche.

●LH concentrations greater than 0.2 to 0.3 mIU/mL (the threshold depends on the assay used) can identify children with progressive CPP with high sensitivity and specificity [19,113-115].

●LH concentrations are less informative in the evaluation of children with nonprogressive or intermittently progressive precocious puberty. While such children typically have basal LH concentrations <0.2 to 0.3 mIU/mL, levels can be in the early pubertal range in some children. Additional clinical characteristics such as lack of progression in secondary sexual characteristics or low LH-to-FSH ratio post-gonadotropin stimulation test can help to differentiate these children from those with progressive CPP. (See 'Laboratory evaluation discordant with clinical presentation' below.)

Care should be used in the interpretation of LH levels in both males and females under the age of two years as gonadotropin concentrations may be elevated at this age in association with the "mini-puberty of infancy" and CPP can be misdiagnosed during this phase of development [10,116].

Basal serum follicle-stimulating hormone — Basal FSH concentrations have limited diagnostic utility in distinguishing children with CPP from those with benign pubertal variants. FSH concentrations are often higher in children with CPP compared with benign pubertal variants, but there is substantial overlap between these groups of children [112,113]. Like LH, FSH concentrations are typically suppressed in children with peripheral precocity.

Serum estradiol — If females, high concentrations of estradiol, with associated suppression of gonadotropins, are generally indicative of peripheral precocity, such as from an ovarian tumor or cyst. Most estradiol immunoassays, however, have poor ability to discriminate at the lower limits of the assay between prepubertal and early pubertal concentrations [117]. More sensitive methods of estimating estradiol concentrations, such as tandem mass spectrometry, distinguish better between prepubertal and pubertal estradiol concentrations [118,119] and should be ordered exclusively. However, further studies are still needed to clarify threshold concentrations. Estradiol need not be routinely measured in males unless examination demonstrates feminization (eg, breast development) or there is unexplained bone age advancement.

Serum testosterone — Testosterone levels are ideally measured between 8 and 10 AM as normative data are based on samples obtained during this time window and low levels at other times of day may be misleading. Elevated testosterone concentrations are indicative of testicular testosterone production in males, or of adrenal testosterone production or exogenous exposure in all children. High concentrations, with associated suppression of gonadotropins, are generally indicative of peripheral precocity. Measurement of other adrenal steroids (eg, dehydroepiandrosterone sulfate [DHEAS]) may be necessary to help discriminate between adrenal and testicular sources of the androgens.

In children with CPP, testosterone immunoassays cannot always distinguish between prepubertal and early pubertal testosterone concentrations, but tandem mass spectroscopy methods are more discriminative [120] (similar to the estradiol assays discussed above), so these should be ordered whenever available.

Bone age — In patients with advanced or progressive development of secondary sexual characteristics confirmed by physical examination, evaluation of skeletal maturation by radiographic assessment of bone age should be performed. Bone age can help with both the differential diagnosis and assessment of whether there may be an impact on adult height. However, in patients presenting with typical features indicative of either isolated premature thelarche or adrenarche, a bone age may not be necessary as initial close clinical observation for pubertal progression is likely sufficient.

A significant advance in bone age (greater than approximately two standard deviations [SD] beyond chronologic age) is more likely to be indicative of either CPP or peripheral precocious puberty rather than a benign pubertal variant. A significantly advanced bone age does not, however, exclude a diagnosis of a benign pubertal variant. As an example, up to 30 percent of children with benign premature adrenarche have bone ages more than two years in advance of their chronologic age [121]. (See 'Benign or nonprogressive pubertal variants' above.)

Subsequent laboratory testing for selected patients — Subsequent laboratory testing depends on the results of the tests outlined above (basal LH, FSH, and estrogen or testosterone) and on the patient's clinical characteristics. Several patient populations will require additional evaluation.

Laboratory evaluation discordant with clinical presentation — In children in whom the clinical picture is discordant with the initial baseline investigations (ie, ongoing pubertal progression with a basal morning LH in the prepubertal range [ie, <0.2 mIU/mL] (see 'Basal serum luteinizing hormone' above)), a gonadotropin-releasing hormone (GnRH) stimulation test may help differentiate those with CPP from those with a benign pubertal variant. This test consists of measurement of serum LH concentrations before and after administration of GnRH. A GnRH agonist may be used instead of GnRH because a single dose of a GnRH agonist has an initial stimulatory effect on the hypothalamic-pituitary-gonadal axis; this alternative is especially convenient when GnRH is not available (as is the case in the United States). Of note, response to GnRH stimulation testing may be bunted in females with BMI >85^th percentile [104,122].

A common protocol is as follows:

●Blood is sampled at baseline for LH, FSH, and either estradiol in females or testosterone in males.

●The child is then given a single dose of GnRH at a dose of 100 mcg or the GnRH agonist leuprolide acetate at a dose of 20 mcg/kg.

●LH is measured at 30 to 40 minutes post-GnRH or 60 minutes post-GnRH agonist [123-125]. Other protocols employ sampling every 30 minutes for up to two hours [123,126], testing of estradiol or testosterone 24 hours later [127,128], or use of other GnRH agonists [129].

The results are interpreted as follows:

●Peak stimulated LH – The optimal cutoff value of peak stimulated LH for identifying children with CPP has not been established and varies somewhat among assays. For most LH assays, a value of 3.3 to 5 mIU/mL defines the upper limit of normal for stimulated LH values in prepubertal children [123,130]. Stimulated LH concentrations above this normal range suggest CPP.

●Peak stimulated LH-to-FSH ratio – Children with progressive CPP tend to have a more prominent LH increase post-stimulation and higher peak LH-to-FSH ratios compared with those with non- or intermittently progressive precocious puberty [127,131]. While a definite diagnostic threshold has not been well defined, a peak LH-to-FSH ratio >0.66 is typically seen with CPP, whereas a ratio <0.66 suggests nonprogressive precocious puberty [131].

●Stimulated estradiol/testosterone – Children with progressive CPP tend to have higher stimulated serum estradiol and testosterone concentrations when measured 24 hours after administration of GnRH or GnRH agonist [127,128]. However, the disadvantage of requiring venipunctures on two consecutive days as well as the lack of consistent published diagnostic thresholds limits the clinical utility of these measurements.

As with basal LH levels, care must be taken in interpreting the results of GnRH stimulation test in children under the age of two years, as both basal and stimulated LH levels can be elevated as part of the normal hormonal changes associated with the mini-puberty of infancy [116].

Signs of androgen excess — In children with precocious pubarche (ie, development of pubic hair), measurement of adrenal steroids may be necessary to help distinguish between peripheral precocity and benign premature adrenarche. Children with premature adrenarche can have mild elevation in adrenal hormones, with DHEAS concentrations of 40 to 135 mcg/dL (1.1 to 3.7 micromol/L), and testosterone levels ≤35 ng/dL (1.2 nmol/L) [132]. (See "Premature adrenarche", section on 'Laboratory tests'.)

DHEAS or testosterone concentrations above these thresholds (and/or other signs of androgen exposure such as enlargement of genital structures and voice deepening) warrant further investigation for causes of peripheral precocity, such as congenital adrenal hyperplasia and virilizing adrenal tumors. An early-morning 17-hydroxyprogesterone (17-OHP) value >200 ng/dL (6 nmol/L) has a high sensitivity and specificity for nonclassic congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency [133-135], although an adrenocorticotropic hormone (ACTH) stimulation test is still needed to confirm the diagnosis. A 17-OHP >1500 ng/dL (45 nmol/L) is essentially diagnostic for nonclassic congenital adrenal hyperplasia. By contrast, a mildly elevated 17-OHP between 115 and 200 ng/dL (4.1 to 6.0 nmol) is more consistent with a diagnosis of benign premature adrenarche. (See 'Adrenal pathology' above.)

Features of genetic disorders — We do not recommend routine genetic testing for most patients with CPP given its limited diagnostic utility and the fact that it generally does not alter clinical management. However, targeted genetic testing may be appropriate when additional clinical features are present. For example, testing for alterations in gene expression in the 14q32.2 region may be considered in a child with developmental delay, a history of being small for gestational age (SGA), and short stature to evaluate for Temple syndrome. Similarly, in cases with a strong family history of paternally inherited precocious puberty, testing for variants in MKRN3 may be warranted.

Notably, confirmatory genetic testing is not required in patients with a clinical diagnosis of McCune-Albright syndrome (MAS), though it may be pursued in patients with some features of MAS (eg, fibrous dysplasia in only one bone) in whom the diagnosis cannot be made based on clinical and radiographic evaluation alone [67]. Genetic sequencing of GNAS in the peripheral blood is limited because of the mosaic distribution of pathogenic gain-of-function variants. Therefore, sequencing of affected tissues or use of highly sensitive sequencing modalities may be used [67,136].

Other populations

●Suspected hCG-secreting tumor – Human chorionic gonadotropin (hCG) can be measured in males to evaluate for the possibility of an hCG-secreting tumor leading to peripheral precocity (eg, if a testicular mass is identified) (see "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors", section on 'Clinical manifestations'). If a tumor is found in the anterior mediastinum, a karyotype should be performed to evaluate for Klinefelter syndrome because of its association with mediastinal germinoma [63]. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum", section on 'Klinefelter syndrome'.)

●Hypothyroidism – Thyroid-stimulating hormone (TSH) should be measured if chronic primary hypothyroidism is suspected as the underlying cause for the sexual precocity. (See 'Primary hypothyroidism' above and "Acquired hypothyroidism in childhood and adolescence", section on 'Adverse effects'.)

Emerging approaches — Emerging biochemical testing strategies to identify cases of progressive CPP include first-morning urinary gonadotropin levels, serum inhibin B, kisspeptin, and irisin levels [137-142]. These tests require further validation before being used routinely in clinical practice.

Imaging — Imaging is not required for all patients with precious puberty. Cases in which imaging should be performed are discussed below.

Patients with central precocious puberty

●Brain MRI – Indications for performing a contrast-enhanced brain MRI depend on patient characteristics, which predict the risk of CNS abnormalities (see 'Central nervous system and pituitary lesions' above):

•Males – For all males with CPP (ie, onset <9 years), perform MRI because of relatively high rates of CNS abnormalities.

•Females – For females with CPP, our approach to imaging depends on the age of onset:

-Onset <6 years – Perform MRI because of relatively high rates of CNS abnormalities in this age group.

-Onset between six and seven years of age – Whether to routinely perform MRI for this group is less clear because data are conflicting about the risk for CNS pathology. In a 2018 meta-analysis, the prevalence of intracranial lesions was 3 percent among females presenting with CPP after six years of age, compared with 25 percent among those presenting before six years [143]. By contrast, some studies not included in this meta-analysis have reported higher rates of MRI brain abnormalities for females with CPP onset after six years of age, with one report of abnormalities in as many as 59 percent of subjects, although only 10 percent had brain tumor or tumor-like lesions [24,144].

Because there are not clear methodologic or population-based reasons for the disparities in reported rates of pathology, recommendations around imaging in this age group remain controversial. A younger age of onset of pubertal signs and higher basal LH and estradiol concentrations have been proposed as predictive features for intracranial pathology [24,25,145]. Still, because these features and clinical suspicion have been shown to have variable sensitivity to detect females with abnormal brain MRIs, some have recommended imaging for all females with CPP regardless of age of onset [24,26,144,146].

-Onset between seven and eight years – Our usual practice is to not perform MRI for those with normal tempo and sequence of pubertal development and no clinical evidence of CNS pathology, especially if there is a family history of earlier pubertal onset.

●Pelvic ultrasound – Pelvic ultrasonography may be a useful adjunct investigation to help differentiate between CPP and benign pubertal variants, especially when the evaluation remains equivocal. Females with CPP have greater uterine and ovarian volumes compared with females who are prepubertal or those with premature thelarche [147-150]. Diagnostic thresholds for uterine and ovarian volumes have been proposed; however, these are variable and some studies have suggested that there is considerable overlap between patients with and without CPP [147,148].

Patients with peripheral precocious puberty

●In females with progressive peripheral precocious puberty, a pelvic ultrasound should be performed to help identify the presence of an ovarian cyst or tumor. As noted above, the presence of a normal ovarian ultrasound does not exclude a diagnosis of a functional ovarian cyst, because the cyst may have regressed by the time of the study. (See 'Benign prepubertal vaginal bleeding' above.)

●Ultrasound examination of the testes, especially if asymmetric in size, should be performed in males with peripheral precocity to evaluate for the possibility of a Leydig cell tumor.

●In females and males, peripheral precocity and progressive virilization and/or markedly elevated serum adrenal androgens (eg, DHEAS) occasionally are caused by an adrenal tumor. If other diagnoses such as congenital adrenal hyperplasia and exogenous androgen or testosterone exposure have been excluded, such patients should have an ultrasound or computed tomography (CT) of the adrenal glands.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Normal puberty and puberty-related disorders".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Early puberty (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Precocious puberty is defined as the onset of pubertal development more than 2 to 2.5 standard deviations (SD) earlier than the average age (figure 1A-B). (See 'Definition' above.)

●Classification – The etiology of precocious puberty is classified by the underlying pathogenesis into three categories (see 'Classification based on etiology' above):

•Central precocious puberty (CPP) is caused by an early activation of the hypothalamic-pituitary-gonadal axis. CPP is idiopathic in 80 to 90 percent of females and 25 to 80 percent of males; the remainder have pathologic causes (eg, brain tumor) (table 1). (See 'Causes of central precocious puberty' above.)

•Peripheral precocious puberty is caused by gonadotropin-independent secretion of sex hormones from the gonads, abnormal production of sex hormones by the adrenal glands, ectopic human chorionic gonadotropin (hCG) production by a germ-cell tumor, or exposure to exogenous sex steroids (table 2). (See 'Causes of peripheral precocious puberty' above.)

•Benign pubertal variants include isolated breast development (premature thelarche), isolated pubic hair development (premature pubarche/adrenarche), benign prepubertal vaginal bleeding, and nonprogressive precocious puberty (table 3). These patterns are usually a variant of normal puberty but require close follow-up for signs of progression. (See 'Benign or nonprogressive pubertal variants' above.)

●Whom to evaluate – Because of the trend of earlier pubertal development, there is controversy about the lower age limit for normal pubertal development. Our approach is to pursue an evaluation in children presenting with secondary sexual development younger than eight years in females or nine years in males (figure 5). Decisions regarding the evaluation of a child with precocious puberty should incorporate all available clinical information; earlier pubertal development should not be simply attributed to a young person's weight status or racial/ethnic background. (See 'Definition' above and 'Evaluation' above.)

●Initial evaluation – The first step is a focused history and physical examination with pubertal staging. If this evaluation confirms advanced or progressive development of secondary sexual characteristics, additional evaluation is warranted. (See 'History and physical examination' above.)

•Initial testing – For children with advanced or progressive development of secondary sexual characteristics on examination, the next step is to measure basal (unstimulated) luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol and/or testosterone concentrations. Results can differentiate between CPP and peripheral precocity, which then guide additional testing (algorithm 1 and table 4).

-Elevated LH (greater than or equal to 0.2 to 0.3 mIU/mL, depending on the assay) suggests CPP. By contrast, LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral precocity or a benign pubertal variant. (See 'Basal serum luteinizing hormone' above.)

-FSH has limited diagnostic utility in identifying children with CPP but is typically suppressed in children with peripheral precocious puberty. The utility of estradiol and testosterone concentrations in diagnosing CPP is dependent on the measurement method used. (See 'Initial tests' above.)

-Bone age – We perform a radiographic assessment of bone age to assess the impact of early puberty on growth prediction and as a means for monitoring progression. (See 'Bone age' above.)

●Further laboratory evaluation for selected patients – Patients in whom additional testing is warranted include those in the following groups:

•Initial laboratory evaluation is discordant with clinical presentation – In these cases (eg, ongoing progression of breast development or testicular enlargement with a prepubertal basal LH level <0.2 mIU/mL), a GnRH stimulation test can be performed to help distinguish CPP from a benign pubertal variant. Children with CPP have a pubertal (heightened) LH response to GnRH stimulation (table 4). (See 'Laboratory evaluation discordant with clinical presentation' above.)

•Signs of androgen exposure – In patients with dehydroepiandrosterone sulfate (DHEAS) or testosterone concentrations that are significantly elevated (and/or other signs of androgen exposure such as enlargement of genital structures and voice deepening), an additional evaluation is warranted to evaluate for virilizing disorders (eg, congenital adrenal hyperplasia due to 21-hydroxylase deficiency). (See 'Signs of androgen excess' above.)

•Genetic testing only in patients with features of genetic disorders – We do not recommend routine genetic testing for most patients with CPP given its limited diagnostic utility and the fact that it generally does not alter clinical management. However, targeted genetic testing may be appropriate when patients have a family history or clinical features suggestive of a genetic etiology. (See 'Features of genetic disorders' above.)

•Other clinical features suggestive of an underlying diagnosis – Additional biochemical testing may be needed in patients in whom another disorder (eg, HCG-secreting tumor or hypothyroidism) is suspected.

●Imaging – Recommendations for imaging depend on the type of precocious puberty (see 'Imaging' above):

•CPP – All males with CPP should have brain MRI because of the high prevalence of central nervous system (CNS) lesions in this group (table 1). Brain MRI should also be performed in all females with onset of CPP before six years of age; there is ongoing controversy about the need for routine imaging of females with CPP onset between six and eight years of age. (See 'Patients with central precocious puberty' above.)

•Peripheral precocious puberty – Males with peripheral precocious puberty may warrant an ultrasound examination of the testes to evaluate for the possibility of a Leydig cell tumor (table 2). Females with peripheral precocious puberty may warrant a pelvic ultrasound performed to help identify the presence of an ovarian cyst or tumor. (See 'Ovarian disorders (females)' above.)

In females and males, peripheral precocious puberty and progressive virilization and/or markedly elevated serum adrenal androgens (eg, DHEAS) occasionally is caused by an adrenal tumor (table 2). If other diagnoses such as congenital adrenal hyperplasia and exogenous androgen or testosterone exposure have been excluded, such patients should have an ultrasound or computed tomography (CT) of the adrenal glands.

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Paul Saenger, MD, MACE, who contributed to earlier versions of this topic review.